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 Nods, Nalps and Naip: intracellular regulators of bacterial-induced inflammation Chamaillard M; Girardin SE; Viala J; Philpott DJCell Microbiol  2003[Sep]; 5 (9): 581-92The innate immune system is the most ancestral and ubiquitous system of defence  against microbial infection. The microbial sensing proteins involved in innate  immunity recognize conserved and often structural components of microorganisms.  One class of these pattern-recognition molecules, the Toll-like receptors (TLRs),  are involved in detection of microbes in the extracellular compartment whereas a  newly discovered family of proteins, the NBS-LRR proteins (for nucleotide-binding  site and leucine-rich repeat), are involved in intracellular recognition of  microbes and their products. NBS-LRR proteins are characterized by three  structural domains: a C-terminal leucine-rich repeat (LRR) domain able to sense a  microbial motif, an intermediary nucleotide binding site (NBS) essential for the  oligomerization of the molecule that is necessary for the signal transduction  induced by different N-terminal effector motifs, such as a pyrin domain (PYD), a  caspase-activating and recruitment domain (CARD) or a baculovirus inhibitor of  apoptosis protein repeat (BIR) domain. Two of these family members, Nod1 and  Nod2, play a role in the regulation of pro-inflammatory pathways through  NF-kappaB induced by bacterial ligands. Recently, it was shown that Nod2  recognizes a specific peptidoglycan motif from bacteria, muramyl dipeptide (MDP).  A surprising number of human genetic disorders have been linked to NBS-LRR  proteins. For example, mutations in Nod2, which render the molecule insensitive  to MDP and unable to induce NF-kappaB activation when stimulated, are associated  with susceptibility to a chronic intestinal inflammatory disorder, Crohn's  disease. Conversely, mutations in the NBS region of Nod2 induce a constitutive  activation of NF-kappaB and are responsible for Blau syndrome, another  auto-inflammatory disease. Nalp3, which is an NBS-LRR protein with an N-terminal  Pyrin domain, is also implicated in rare auto-inflammatory disorders. In  conclusion, NBS-LRR molecules appear as a new family of intracellular receptors  of innate immunity able to detect specific bacterial compounds and induce  inflammatory response; the dysregulation of these processes due to mutations in  the genes encoding these proteins is involved in numerous auto-inflammatory  disorders.|*Adaptor Proteins, Signal Transducing[MESH]|Animals[MESH]|Apoptosis Regulatory Proteins[MESH]|Bacterial Infections/immunology/*metabolism[MESH]|Enzyme Inhibitors/*metabolism[MESH]|Epithelial Cells/cytology/metabolism[MESH]|Genetic Diseases, Inborn/genetics/metabolism[MESH]|Humans[MESH]|Inflammation/immunology/metabolism/*microbiology[MESH]|Microtubule Proteins/genetics/*metabolism[MESH]|NLR Proteins[MESH]|Nerve Tissue Proteins/genetics/*metabolism[MESH]|Neuronal Apoptosis-Inhibitory Protein[MESH]|Protein Structure, Tertiary[MESH]|Proteins/genetics/*metabolism[MESH]
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